Tag Archives: Myotonic dystrophy

Triplets and TADs

Neurologists have long been interested in triplet diseases — https://en.wikipedia.org/wiki/Trinucleotide_repeat_disorder.  The triplet is made of a string of 3 nucleotides.  Example —  cytosine adenosine guanosine or CAG — which accounts for a lot of them.  We have lots of places in our genome where such repeats normally occur, with the triplets repeated up to 42 times.  However in diseases like Huntington’s chorea the repeats get to be as many as 250 CAGs in a row.  You normally are quite fine as long as you have under 36 of them, and no one has fewer than 6 at this particular location.

Subsequently, expansions of 4, 5, and 6 nucleotide repeats have also been shown to cause disease, bring the total of repeat expansion diseases to over 40.  Why more than half of them should affect the nervous system entirely or for the most part is a mystery.  Needless to say there are plenty of theories.

This leads to three questions (1) there are repeats all over the genome, why do only 40 or so of them expand (2) since we all have repeats in front of the genes where they cause disease why don’t we all have the diseases (3) why do the number of repeats expand with each succeeding generation — the phenomenon is called anticipation.  I saw one such example where a father brought his son to my muscular dystrophy clinic.  The boy had moderately severe myotonic dystrophy.  When I shook the father’s hand, it was clear that he had mild myotonia, which had in no way impaired his life (he was a successful banker).

A recent paper in Cell may help answer the first question and has a hint about the second [ Cell vol. 175 pp. 38 – 40, 224 – 238 ’18 ].  21 of 27 disease associated short tandem repeats (daSTRs) localize to something called a topologically associated domain (TAD) or subdomain (subTAD) boundary. These are defined as contiguous intervals in the genome in which every pair has an elevated interaction frequency compared to loci out side the domain.  TADs and subTADs are measured using chromosome conformation capture assays (acronyms for them include 3C, CCC, 4C, 5C, Hi-C).

Briefly they are performed as follows.  Intact nuclei are isolate from live cel cultures.  These are subjected to paraformaldehye crosslinking to fix segment of genome in close physical proximity. The crosslinked genomic DNA is digested with a restriction endonuclease, and the products expanded by PCR using primers in all possible combinations.  Then having a complete genome sequence in hand, you see what regions of the genome got close enough together to show up in the assay.

This may help explain question one, and the paper gives some speculation about question two — we don’t all have these diseases, because unlike the unfortunates with them, we don’t have problems in our genes for DNA replication, repair and recombination.  There is some evidence for this;  studies in model organisms with these mutations do have short tandem repeat instability.

Unfortunately the paper doesn’t discuss anticipation, because no clinicians appear to be among the authors, even though they’re from Penn which 50+ years ago was very strong in clinical neurology.

None of this work discusses the fascinating questions of how the expanded repeats cause disease, or why so many of them affect the nervous system.

The Kavanaugh Ford confrontation will be to this decade what the Patty Hearst kidnapping was to a previous one  — https://en.wikipedia.org/wiki/Patty_Hearst.  Since I suffered 4 episodes of physical (not sexual) abuse as a kid, and dealt with this extensively as a neurologist, I’m trying to decide whether to write about it.  Emotions are high and there are a lot of nuts out there on the net. There is even a reasonable possibility that both Ford and Kavanaugh are right and not lying.

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Back from the 50th Med School Reunion

Mostly some social notes from my 50th Med School reunion (Penn), but first some serious science.

I did two years of graduate work in chemistry between college and med school, and one of the guys I taught organic to is an academic research neurologist. He told me that they had some encouraging results using antisense oligonucleotides to remove the excessive repeat CTGs from myotonin, the gene defective in myotonic dystrophy. They were able to get it into cells, and even showed some clinical benefit in animal models. So he’s still using chemistry.

Myotonic dystrophy is one of the few triplet expansion diseases that makes sense to me, because unlike most of them, it affects a wide variety of tissues, not just the nervous system.

Just about everyone had a great time at the reunion. On entering med school I was told, that I’d know my classmates better than my spouse. Well, I certainly spent more time with them in the clinical years.

It was a happy time and yet sad as well, as we all knew that this was probably the last time we’d all see each other.

The previous post https://luysii.wordpress.com/2016/05/11/off-to-the-50th/ had a lot about (the lack of) minority representation back then.

Things have improved, as there is now an office of diversity (so Penn is now doing more than paying hypocritical lip service to it — vide Elizabeth Warren).

Our Nigerian classmate came back. He’d spent 17 years back home in Africa but left because he was unable to fight the corruption there, even as a native son. He hassled a black medical student from Africa, finding that she was of the Yoruba tribe, telling her to go back and serve her country (at least for a while).
So things have improved, but not enough. An an affair Friday night, all 5 or so of the blacks present were sitting at the same table. I barged in saying I was bringing some diversity to their table, and initially got some strange looks. But then I told them a few of the events of the previous post and they warmed up. At least the country is  now getting the benefit of their brains.

We’ll know things have really improved, when black physicians feel comfortable enough to mingle with the crowd.

About 65 of the 125 of us were back. Only 18 people were listed as having died, which seems like a very small number for a group of 125 26 year olds 50 years later. I do know of one unreported death of a classmate from AIDS.

This is actually nothing new — and here are my notes on a study done nearly 30 years ago. My speculation is that, docs get a lot of reinforcement, seeing the effects of negative health choices. I doubt that all of it is due to social or economic class, although some must be.

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[ J. Am. Med. Assoc. vol. 259 p. 3158 ’88 ] This is an overview of the Physicians’ Health study in which 22,000 American physicians took either aspirin or placebo in a double blind study. They were only taking 5 grains of aspirin every other day. Cardiovascular mortality was cut, but overall mortality was not. However the group experienced just 88 deaths when 733 would have been expected. . This may be due to a beneficial life style, or social class. Thus the EIGHTFOLD lower mortality throughout makes the study harder to interpret. Amazingly, the authors of the study don’t really focus on why the study group (even those on placebo) did so well, but whether the aspirin added anything extra. What we need is to reduce mortality in our patients eightfold and then worry about giving aspirin.

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Here is a tale of the bad old days for the feminists among you. There were under 10 women in our class of 125. One very bright woman wanted to be a surgeon. She asked Dr. Everett Koop about it. This was when Koop was basically inventing the specialty of pediatric surgery at Children’s Hospital of Philadelphia (CHOP), and long before he became Surgeon General.

He gave her some very hard and very honest advice (this was Koop after all). He told her that the first rate surgery residencies simply were not accepting women. To rise to the true level of her ability, she’d need to choose something else. She didn’t like this one bit, but did follow his advice, went into another field and became department chair at another Ivy League med school.

Lastly two stories about the All American basketball player in our Class (Jerry Gardner Kansas ’62). He’s about 6′ 2″ now, and using a cane as he’d had hip surgery a few months ago. He did note that back then Freshman weren’t allowed to play, so he still has a year of eligibility left. Jerry went to NIH after graduation and established a lab studying GI hormones.

Further proving that time does not heal all wounds, Jerry reminisced about the two foul shots he missed at the tail end of a game in the NCAA final (or semifinal) which might have won them the game. For further examples of the phenomenon see — https://luysii.wordpress.com/2010/10/25/time-does-not-heal-all-wounds/